mpi-0479605 and purine

Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties.

Topics: Cell Cycle Proteins; Cell Proliferation; Drug Design; HCT116 Cells; Humans; Models, Molecular; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Purines; Pyrimidines; Pyrroles; Quinazolines; Structure-Activity Relationship

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.

Topics: Adenine; Administration, Oral; Animals; Apoptosis; Binding Sites; Crystallography, X-Ray; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; M Phase Cell Cycle Checkpoints; Mice; Molecular Conformation; Morpholines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Purines; Structure-Activity Relationship